2-butoxyethyl acetate

Carcinogenicity

Description of key information

Data for the read across substance: 2-butoxyethanol:

NTP 2 year study in rat, inhalation: NOAEL>125ppm (>833mg/m3)

NTP 2 year study in mice, inhalation: NOAEL=125ppm (833mg/m3)

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

833 mg/m³

Justification for classification or non-classification

The species and sex specificity of the neoplastic responses and the current evidence supporting the hypothesis that the likely mode of action leading to the liver hemangiosarcomas in mice following chronic exposure to 2 -butoxyethanol is based on haematotoxicity, then the substance is unlikely to be a human carcinogen.Therefore, an appropriate classification for “No classification” is proposed for carcinogenicity for 2 -butoxyethanol. Since 2 -butoxyethanol is the prime hydrolysis product of 2 -butoxyethyl acetate in vitro, this conclusion can equally be applied with confidence to the latter substance.

Since the only carcinogenic effects can be considered secondary to hemolysis, and hemolysis is the key end point for repeat dose toxicity, no separate risk characterisation is necessary for the cancer end point. If there are no concerns for repeat dose toxicity, it can be considered that there will be no concerns for cancer either.

Additional information

There is no carcinogenicity data available on the substance 2 -butoxyethyl acetate. In view of the rapid hydrolysis of this substance to the parent glycol ether 2 -butoxyethanol under physiological conditions, the carcinogenic potential of 2 -butoxyethyl acetate in vivo is likely to be similar to that of 2 -butoxyethanol. A summary of the data for the latter is presented here.

In a 2 year NTP cancer bioassay rats and mice were exposed to 2 -butoxyethanol by the whole body inhalation route to concentrations up to 125ppm (rats) and 250ppm (mice). There was no evidence for carcinogenicity in male rats. In female rats, the incidence of benign or malignant phaeochromocytoma (combined) of the adrenal medulla in females exposed to the top dose of 125 ppm was not significantly increased compared to the chamber controls, but it did exceed the historical control range. Within this dose group, there was only a single incidence of malignant phaeochromocytoma. This finding is equivocal at worst and cannot be attributed with confidence to exposure. In mice there was limited evidence of carcinogenicity, with a low incidence of forestomach tumours in females and hemangiosarcomas in males at the top dose of 250ppm.

Genotoxicity is not an important toxicological property of this chemical and it is unlikely that the low, variable and uncertainly defined genotoxic activity reported in section 7.6 can be the cause of the carcinogenic responses. Hypotheses have been proposed and supported by experiment data in an attempt to explain the carcinogenic responses, which are described in detail in the study report for this species in chapter 7.7. In the case of forestomach tumours, the argument that they arise in a tissue subject to sustained abuse and consequent repair is clear. It is likely that this finding is in reality not sex specific but merely due to chance that the low level incidence in females rose above the level of statistical significance but it did not do so in males. In the case of the haemangiosarcomas, data from experiments with other chemicals show that mice are more susceptible to haemangiosarcoma development than are rats, and male mice are more sensitive than female mice; the database in support of the hypothesis that life-long exposure of the liver to Kupffer cell pigmentation is a pre-requisite for an increase in liver haemangiosarcoma rates in male mice is small but supportive of the hypothesis. With the rejection of genotoxicity as a possible mechanism, strong evidence for a potential source of reactive oxygen species within the liver, and a mode of action where each step has supporting data, it is reasonable to presume that these play a role in the neoplasia.

With regard to human relevance, the mode of action proposed for the induction of haemangiosarcomas strongly suggests that 2 -butoxyethanol is not likely to present a carcinogenic hazard because human erythrocytes are substantially more resistant to haemolysis than are rodent erythrocytes. The mode of action proposed for the induction of forestomach tumours would also point to a lack of human relevance; it is generally accepted that the relevance for man is low for agents that have no demonstrable genotoxicity and that are solely carcinogenic for the forestomach squamous epithelium in rodents after oral administration. Whilst 2 -butoxyethanol does not fully satisfy these conditions, there are proposed mechanisms that are supported by experimental evidence to show how this chemical, even when inhaled, can accumulate in the forestomach contents, where it can remain for many hours to cause damage directly or after its metabolism to butoxyacetic acid. The NTP study also showed no evidence of irritation to the mouse glandular stomach, oesophagus or oral squamous epithelia which again supports a lack of relevance to humans.

Since the only carcinogenic effects can be considered secondary to hemolysis, and hemolysis is the key end point for repeat dose toxicity, no separate risk characterisation is necessary for the cancer end point. If there are no concerns in humans for repeat dose toxicity, it can be considered that there will be no concerns for cancer either.

Carcinogenicity: via inhalation route (target organ): digestive: liver; digestive: other